Alkamine derivatives of ethers of p-hydroxymethyl benzoic acid



Patented June 6,

" ALKAMINE DERIVATIVES OF ETHERS OF D -HYDROXYMETHYL BENZOIQ ACID Victor 5. Salvin, Cumberland, Md., and Arthur J. Hill, New Haven, Conn, assignors to American Cyanamid Company, New York, N. Y., a

corporation of Maine No Drawing. Application April 16, 1942, Serial No. 439,234

16 Claims.

This invention relates-to the alkyl esters of palkamineoxy-methyl benzoic acid and to methods of preparing the same.

According to the present invention we have found that a new series of compounds can be prepared, many of which have high potency as local anesthetics for surface and introcutaneous use, some of which compounds have activities comparable to cocaine accompanied with lower toxicity. The compounds of the present invention are alkyl esters of p-alkamineoxymethyl benzoic' acids and may be represented by the following formula:

CHzOR COOAlk in which Alk is an alkyl radical and R is an alkamine, the ether oxygen being joined to a carbon atom of the alkamine group. The alkamine group may be a secondary or tertiary amine but the most important products covered by the present invention are those in which the alkamine is tertiary which may be represented by the following formula:

Alka CflaOAlkaN Alk.

COOAlk in whlchAlk is an alkyl radical, Alkz is an alkylene radical, and Alka and Alk are the same or different alkyl groups. The alkylene radical, Alkz, may be straight chain or branch chain.

While the products of the present invention are not limited to any particular method of preparation, I prefer to use a process in Which an ester of p-halogen methylbenzoic acid is reacted with an alcoholate of the desired aminoalcohol; The reaction proceeds smoothly with good yield, and in a more specific aspectthe preferred process is included in the present invention.

The cheapest intermediates to use are the p-- chloromethylbenzoic acid esters, but the p-brommethyl compoundlmay also be used, the reactlon proceeding with excellent yield and great ease, but for most compounds the additional cost of the brom intermediate over the chlor intermediate is not warranted.

The esters of the present finvention are secondary or tertiary amines and form the usual salts such as hydrochlorides sulfates, borates and the like. The salts of the bases are therefore included in the invention and in fact the crude product obtained by extraction-with dilute hydro- V chloric acid is the hydrochloride rather than the free base. Quaternary nitrogen salts may also be prepared such as for example the methiodides, ethobromides and the like.

The invention will be described in greater detail in conjunction with the igllowing specific examples which are typical illustrations. The parts are by weight.

' EXAMPLE]. Ethyl-p 9-diethylaminoethoizzymethz/l benzoate cement-capsicum COOCzH;

23 parts of sodium are dissolved in 250 parts oi fi-diethylaminoethanol which' 'represents an excess of the alcohol. After formation of the alcoholate excess amino alcohol is removedby distillation under reduced pressure and 1500 parts of dry benzene added to the residual salt. 98 parts of ethyl p-chlormethyl, :benzoatedissolved in 600 parts of benzene are then slowly added with stirring, the temperature of the reaction mixture being maintained jsufiiciently high throughout the addition so that gentle refluxing of the benzene takes place. EAiter all of the ester is added, refluxing is maintained for a considerable period until the reaction is complete.

The benzene reaction mixture is then extracted with cold dilute hydrochloric acid and the extract neutralized with a slight excess of sodium hydroxide in order ,.to precipitate the basic oils which are then extracted with ether, the extract washedwith water, dried and :the ether removed by distillation. A residual liquidremains which contains the desired product together with a certain amount of unreacted amino alcohol; Distillation is effected at reduced Iapressure (4 mm.) the amino alcohol coming off first and the alkamine ether ester coming oil-in a fraction boiling between and C. This fraction is then redistilled and a straw colored oil is obtained in good yield and. boiling in the range of 176-178" C. at 4 mm. The product-showssanesthetic activity comparable to cocaine with much lower toxicity.

O OCzHs of 'y-diethylaminopropanol and-the excess'amino alcohol is removed by distillation under reduced pressure. 500 parts of benzene were then added and 198 parts of ethyl-p-chlormethylbenzoate dissolved in 500 parts of benzene gradually introduced into the solution with continuous agitation. Reaction starts immediately, the reaction mixture heats up and a solid (sodium chloride) precipitates.

23 parts of sodium are dissolved in 320 parts (200 parts) of B-diethylaminoethanl.

After the addition of all of the ester the reactionv mixture is refluxed and stirred for a considerable period until no more solid precipitates.

- The reaction mixture is thencooled and extracted with cold dilutehydrochloric acid. This acidv lextract containing the hydrochloride-of the alkaline ether ester is then made alkaline with solid sodium carbonate and the liberated alkalineether ester extracted with ether. After drying the ether extract, the ether is removed and the residual liquid purified by fractional disti llation under reduced -pressure(3 mm). At first some unreacted amino alcohol 'distills off and the ether ester fraction thencomes over at about 175 to 180 C. yielding a-product' which on redistillation is a light colored liquid boiling at 177 to 179 C. (3 mm.) .The yield is slightly under 50%. A considerable portion of the remainder of the reactants can be recovered in the form of a high boiling fraction boiling about 200 C. (3 mm.) and constitutesa symmetrical 'y-diethylaminopropylether ester, the ethyl grouping having been replaced with amino alcohol by alcoholysis. The product is a. useful pharmaceutical, showing anesthetic activity slightly less than that of Example 1 with the same low toxicity.

I EXAMPLE 3 Ethyl-12w dibutylaminopropoagymethyl benzoate CH:0CH3-CH2C H3N(C4H9)T oooclnr The process of Examples .1 and 2 is followed except that 460 parts of .y-dibutylaminopropanol is substituted for'320' partsof cy-diethylaminopropanol. After extracting with hydrochloric acid, neutralizing and extracting withether, a liquid is obtained which is fractionally distilled. At first some unreacted amino alcohol comes over and the major portion of: the liquid then distills from 195-199? C. -(3 'mm.).- On IBdiSrtillation the boiling range'can be reduced to 196-198 C. at the same pressure. A considerable by-product is obtained as a high boiling fractioncoming over at above 232 0. As in the case of Example 2 this fraction represents a by-productin, which the amino alcohol has replaced ethyl alcohol in theester group by alcoholysis. This by-product is also a useful pharmaceutical and showsslightly lower .anes thetic activity than Example 1, but still lower toxicity.

} pressure and 500 parts benzene added. of butyl-p-chloromethyl benzoate (prepared by 2,350,826 u EXAMPLE 4 Butyl-p-p-diethylaminoethowymethyl benzoate CHzOCHz-CHr-N(C:He)l 5 C00C4Ho '12 parts of sodium are dissolved in an excess The excess amino alcohol is then removed under reduced parts esterifying p-chloromethylbenzoic acid with butanol) are dissolved in 500 parts of benzene and the solution added gradually to the alcoholate solution. The mixture heats up and after all of the ester is added refluxing is continued until the reaction is complete which takes several days. The reaction mixture is" 'cooled,= extractedwi th dilute hydrochloric acid and the acid extract newtralized with sodium carbonate liberating the urireacted amino alcohol and the amino ester. The solution is then extracted with ether and th'e ether extract dried, ether'removed and the'residual liquid subjected to fractional distillation a't low pressure (2 mm.). Unreacted amino alcohol comes over first and the desired ester is 'obtained in a fraction boiling between an'd175" C. which on redistillation has'a boiling range of 173-1'74 C. It is a faintly yellow oil, the yield being approximately 50%. The product is a more active local anesthetic than cocaine with greatly reduced toxicity. A high'boiling fraction coming over above C. is also obtained which is the corresponding alkamine ester produced by alcoholysis of the ether ester with excess amino alcohol. This product is also a useful pharmaceutical. r w EXAMPLE5. Butyl-p-fi-diethylaminopropoxylmethyl ber z'zo'a'te CHgO-OHPCH-N' The procedure of Example 4' is followed using corresponding amounts of fl-diethylaminopropanol in place of the fl-diethylaminoethanol. The product obtained is a -1ight'colored oil having properties closely resembling that of the corre; sponding fl-diethylaminoethoxyniethyl compound. Alcoholys is also takes place producing a consid erable quantity of a. high boiling fraction in which the diethylaminopropanol has replaced the butyl radical by alcoholysis.

V The examples describe alkamine ether 'e'ster s or some of the more common'amino alcohols; The reaction by which the ether esters are made, how ever, is quite general and applicable to any amino alcohol which is capable of formin'g'alcoholates'. It should also be noted that the'substituents' on the nitrogen do not have to-separate alkyl chains but may form part of-"a' ring such as a piperidine or morpholine ring. "Examples-of other alcohols which can be used to prod-uee the corresponding ether esters are the dibutylaminobutanols, findphenylethylaminoethanol, ;3-dipr opylaminoethae nol, fl-morpholinoethanol I ,B-piperidinoethanol, p-dicyclohexylaminoethanol 3 methylcyclohex ylaminoethanol, p-phenylaminoethanol, fifi-dimethyl-'y-piperidinopropanol and the like.

We claim:

1. An -ester oi. p-di-alkylaminoalkoxymethyl benzoic acid.

2. An ester of a p-dialkylaminoalkoxymethyl benzoic acid having the following formula:

Alk'

CHaORN COOAlkl in which R is an alkylene radical and Alk', Alkz and Alk: are alkyl groups.

3. An ester of a p-(omega-dialkylaminoalkoxymethyl) benzoic acid having the following formula:

in which A1k-, Alkz and Alka are alkyl groups.

4. A salt of an ester according to claim 2.

5. A salt of an ester according to claim 3.

6. An ester 01' p-fl-diethylaminoethoxymethyl benzoic acid.

7. A salt of an ester of p-p-diethylaminoethoxymethyl benzoic acid.

10 alkylaminoalkoxymethyl benzoic acid which comprises reacting a p-halogen-methyl alkyl benzoate with an alcoholate of an alkylamino alcohol.

13. A method of preparing an alkyl ester of a 15 dialkylaminoalkoxymethyl benzoic acid which comprises reacting an alkyl ester of p-halogenmethyl benzoic acid with an alcoholate of a dialkylamino alcohol.

14. A method of preparing ethyl p-fi-diethylgo aminoethoxymethyl benzoate which comprises reacting ethyl p-chlormethyl benzoate with an alkali metal alcoholate or p-diethylaminoethanol.

15. A method of preparing p-fi-diethylaminoethoxymethyl benzoate which comprises reacting g5 butyl p-chlormethyl benzoate with an alcoholate of p-diethylaminoethanol.

16. A method of producing butyl p-w-dibutyL- aminopropoxymethyl benzoate which comprises reacting butyl p-chlorme'thyl benzoate with an 30 alcoholate or -dibutylaminopropanol.

(VICTOR s. SALVIN.

ARTHUR J. HILL.

Certificate ,of Correction Patent No. 2,350,826. Jill 1e 6, 1944.

VICTOR S. SALVIN ET AL.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows: Page 3, second column, lines 56, claim 10, for "p-y-dibutylaminopropoxy" read p-v-dt'butylaminoproporg methyl; and that the said Letters Patent should be read with this correction therein that the same may conform tothe record of the case in the Patent Oflice.

Signed and sealed this 7th day of November, A. D. 1944.

[SEAL] LESLIE FRAZER,

Acting Commissioner of Patents. 

